The transcriptional coactivator PGC-1alpha plays a central role in lipid metabolism; although its specific regulatory functions have been extensively studied, not much is known about the identity of potential interacting regulators that could switch on/off its activity in response to metabolic cues. We have taken a biochemical approach followed by mass spectrometry and recently characterized a novel PGC-1alpha binding molecule that is able to enhance PGC-1alpha's transcriptional activity in vitro. We are currently performing gain-and loss-of-function experiments assessing the effects of this novel cofactor on the expression of genes regulated by PGC-1alpha and we are determining its overall effects on lipid beta-oxidation in vivo.In addition, we have screened the PGC-1alpha promoter to identify novel transcriptional pathways that turn on PGC-1alpha expression. We are currently validating the binding of these candidate factors and assessing the effects of their activation on energy balance.